PROJECT SUMMARY AND RELEVANCE Project: The incidence of kidney cancer has tripled due to increased detection of small (<4 cm), asymptomatic tumors. While current guidelines recommend resection in patients fit for surgery, this is not supported by high-level evidence. Active surveillance (close imaging observation) for small renal tumors is an alternative method to limit harms associated with unnecessary/overtreatment including perioperative complications and the development of chronic kidney disease. When observed, small tumors rarely demonstrate rapid growth and delayed intervention is always an option. A significant barrier exists in the adoption of active surveillance there are no reliable methods to determine a small tumors' biologic aggressiveness. Genomic alterations can now be assessed from a renal tumor biopsy. However a major obstacle to a personalized medicine approach are concerns raised over tumor heterogeneity from the study of large, metastatic kidney tumors. The extent of hetereogeneity in small renal tumors and its clinical relevance is currently unknown. Using existing data from the Cancer Genome Atlas, we will examine the extent of global heterogeneity in various forms of kidney cancer and its association with tumor size and prognosis. By performing multi-region sequencing, we will investigate regional differences in common driver mutations and the overall extent of heterogeneity in freshly, resected and archived renal tumors. This research will provide insight on the clinical significance of tumor heterogeneity and lay the foundation for biopsy based biomarker research involving the small renal mass. If successful, this approach could limit overtreatment and spare patients' unnecessary treatment morbidity as well as decreasing the economic burden of this cancer (an estimated $5 billion /year). Candidate: I am a urologic surgeon focused on kidney cancer. After residency, I completed a urologic oncology fellowship at the NCI, which provided unique clinical training in kidney cancer. As a new faculty member at Yale, I hope to obtain mentorship and didactic research training in genetics, bioinformatics, and biomarker development. I will harness this experience to become an independent investigator focused on genomic biomarkers in kidney cancer and apply it to uncertain clinical scenarios such which small tumors actually require treatment. I have selected an accomplished and multi-disciplinary mentorship team. My primary mentor, Dr. Harriet Kluger is focused on molecular biology and biomarker discovery in advanced kidney cancer. Other mentors, Drs. Murat Gunel and Yuval Kluger, provide expertise in genetics and bioinformatics, respectively. This diverse mentorship team along with an outstanding didactic training plan will enhance my ability to conduct independent translational research. This research experience will synergize with my clinical expertise to provide me with the necessary tools to investigate the current dilemmas in early stage renal tumors.